Genetic aspects of Charcot-Marie-Tooth disease

Historical perspective and nomenclature

In 1886 Drs Charcot and Marie of France and Dr Tooth of England described patients with an inherited form of peroneal muscular
atrophy, characterised by a progressive weakness and atrophy of distal muscles, usually originating in the feet and lower
legs and progressing to the hands and forearms—a disorder now known as Charcot-Marie-Tooth (CMT) disease. Early literature
attested to the existence of several distinct disorders in addition to CMT disease, including Dejerine-Sottas syndrome (DSS)
and Roussy-Lévy syndrome, but histopathological evidence combined with the advent of electrodiagnostic testing and molecular
investigation have demonstrated that these syndromes are clinical variants of CMT disease.

Key messages

The duplication of a 1.5 Mb DNA fragment encompassing the PMP22 gene on chromosome 17p11.2 is associated with over 70% of CMT1 cases

Point mutations of the PMP22,P0, and Cx32 genes are also associated with the CMT1 phenotype

PMP22 and P0encode myelin proteins which have important roles in the compaction of myelin. Cx32 encodes a gap junction protein which is considered to allow trafficking of metabolites and secondary messengers between the
non-compact layers of myelin. Murine models have validated the hypothesised roles of these proteins

CMT disease is extremely heterogeneous, with at least eight additional loci identified. No genes have as yet been identified
at these loci

The term CMT disease is now applied to a range of hereditary peripheral neuropathies, with a population prevalence of approximately
one in 2500, which are able to be differentiated at several levels. None the less, the nosology surrounding CMT disease remains
confusing and is further confused by the term hereditary motor and sensory neuropathy (HMSN), introduced to describe a broad
range of neurological disorders with both motor and sensory involvement.

Classification of CMT disease

NERVE CONDUCTION STUDIES AND PATHOLOGY

A major differentiating factor between the different forms of CMT disease is identified by …